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* From the University of Rochester School of Medicine and Dentistry, Cancer Center and Department of Microbiology and Immunology, Rochester, NY.
Correspondence to: Richard P. Phipps, PhD, University of Rochester Cancer Center, Box 704, 601 Elmwood Ave, Rochester, NY 14642; e-mail: Richard_Phipps{at}urmc.rochester.edu
Lung injury may occur as a consequence of trauma, infection, occupational exposure to respiratory toxicants, or cancer therapy. No matter what the insult, lung injury must be resolved. Tissue repair begins with the coagulation cascade and the activation of platelets. This is followed by the release of inflammatory mediators important for chemotaxis of WBCs and activation of resident cells involved in the wound repair process, ie, endothelial cells, epithelial cells, and fibroblasts. The remodeling phase is primarily dependent on the ability of the fibroblast to synthesize and degrade extracellular matrix components. An adequate wound healing response results in minimal scarring and maintenance of normal lung architecture and function. Dysregulation at any point of this process can lead to extensive scarring and loss of function.
Fibroblasts are much more than a source of scaffolding. They are key cells in the wound repair process. They participate in the immune response by producing (and responding to) cytokines and chemokines that initiate the recruitment and retention of bone marrow-derived immune effector cells. The ability of lung fibroblasts to be "activated" to secrete inflammatory mediators is under investigation. We have found that CD40 is a crucial element in the process of lung fibroblast activation. CD40 is a 45-kd to 50-kd type I membrane glycoprotein originally described on the surface of B lymphocytes.1 CD40 is the cognate receptor for CD40 ligand (CD154), an approximately 33-kd member of the tumor necrosis factor family of cytokines initially thought to be exclusive to activated CD4+ T cells.1 Cells known to express CD40 include antigen-presenting cells such as B lymphocytes and dendritic cells,1 as well as non-bone marrow-derived cells like fibroblasts and keratinocytes.2 3 These cells interact with CD40 ligand-expressing cells such as T cells,1 mast cells,1 and activated platelets.4 Recently, platelets were shown to contain preformed CD40 ligand that translocates to the cell surface within seconds of activation by thrombin.4
CD40 is known to be an important "activation" molecule for all cells that express it. CD40 engagement sends a potent signal to B lymphocytes, regulating many aspects of the life and death of the cell. For example, CD40 ligation of B cells can induce proliferation, expression of the B7 costimulatory molecules, class switching to make IgE, and rescue from apoptosis in germinal centers.1 CD40 engagement on dendritic cells induces their maturation.1 Non-lymphoid–derived cells, such as fibroblasts, are also known to express CD40 and respond to CD40 ligation.2 5 6 7 8
Fibroblasts are a heterogeneous group of dynamic cells that
express functional CD40.2
5
Fibroblasts respond to CD40
ligation by increasing their expression of the adhesion molecules
intercellular adhesion molecule-1 and vascular cell adhesion
molecule-16
and producing inflammatory
mediators.5
7
We have previously shown that human
fibroblasts stimulated with CD40 ligand are activated to synthesize the
proinflammatory cytokines interleukin (IL)-1, IL-6, and IL-8,
cyclo-oxygenase-2, prostaglandins, and extracellular matrix proteins
such as hyaluronate.5
7
8
IL-6 is found in abundance in
inflammatory responses and has been shown to be an autocrine growth
factor for lung fibroblasts.9
IL-8 is a chemotactic factor
for neutrophils and T cells. The generation of these inflammatory
mediators occurs mainly through nuclear factor-
B–mediated
mechanisms.10
Interferon-
, a cytokine found at high
levels at sites of inflammation, upregulates CD40 display on human
fibroblasts in vitro.2
5
7
This correlates with
in situ data that CD40 expression is significantly higher in
acutely inflamed as compared with uninflamed tissue.7
A model for fibroblast CD40 signaling, and the regulation of pulmonary inflammation and fibrosis is presented in Figure 1 . Normally, lung fibroblasts express low levels of CD40 on their surface, and there are few CD40 ligand-expressing cells in the vicinity. Tissue injury allows platelets and plasma to penetrate the endothelial cell boundary. Platelets may initiate the inflammatory phase of the wound healing process by engaging fibroblast CD40 via their surface/secreted CD40 ligand. In the inflammatory microenvironment, fibroblasts are induced to express high levels of CD40. Inflammatory cells, such as T and mast cells, migrate into the wound and interact with fibroblasts via CD40 ligand. This induces fibroblasts to proliferate, produce cytokines, and repair the injured tissue by laying down extracellular matrix components.
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Footnotes
Abbreviation: IL = interleukin
This research was supported by United States Public Health Service grants DE11390, HL56002, CA11051, EY08976, DE07061, T32AI07285, HD01332, the University of Rochester Cancer Center Discovery Fund, and the Pepper Center.
References
This article has been cited by other articles:
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  F. Nimmerjahn, D. Dudziak, U. Dirmeier, G. Hobom, A. Riedel, M. Schlee, L. M. Staudt, A. Rosenwald, U. Behrends, G. W. Bornkamm, et al. Active NF-{kappa}B signalling is a prerequisite for influenza virus infection J. Gen. Virol., August 1, 2004; 85(8): 2347 - 2356. [Abstract] [Full Text] [PDF]
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 J. Kaufman, P. J. Sime, and R. P. Phipps Expression of CD154 (CD40 Ligand) by Human Lung Fibroblasts: Differential Regulation by IFN-{gamma} and IL-13, and Implications for Fibrosis J. Immunol., February 1, 2004; 172(3): 1862 - 1871. [Abstract] [Full Text] [PDF]
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S. Bordin and D. Whitfield Cutting Edge: Proliferating Fibroblasts Respond to Collagenous C1q with Phosphorylation of p38 Mitogen-Activated Protein Kinase and Apoptotic Features J. Immunol., January 15, 2003; 170(2): 667 - 671. [Abstract] [Full Text] [PDF]
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